EP0912570B1 - Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors - Google Patents

Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors Download PDF

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Publication number
EP0912570B1
EP0912570B1 EP97930518A EP97930518A EP0912570B1 EP 0912570 B1 EP0912570 B1 EP 0912570B1 EP 97930518 A EP97930518 A EP 97930518A EP 97930518 A EP97930518 A EP 97930518A EP 0912570 B1 EP0912570 B1 EP 0912570B1
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group
benzyl
pyrido
compound
methyl
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French (fr)
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EP0912570A1 (en
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George Stuart Glaxo Wellcome Plc Cockerill
Malcolm Clive Glaxo Wellcome Plc Carter
Stephen Barry Glaxo Wellcome Plc Guntrip
Kathryn Jane Glaxo Wellcome Plc Smith
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Glaxo Group Ltd
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Priority claimed from GBGB9625492.5A external-priority patent/GB9625492D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine.
  • the invention relates to bioisosteres of quinoline and quinazoline derivatives which exhibit protein tyrosine kinase inhibition.
  • Protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A.F. Wilks, Progress in Growth Factor Research, 1990, 2 , 97-111; S.A. Courtneidge, Dev. Supp.l, 1993, 57-64; J.A. Cooper, Semin. Cell Biol., 1994, 5(6) , 377-387; R.F. Paulson, Semin. Immunol., 1995, 7(4) , 267-277; A.C. Chan, Curr. Opin. Immunol., 1996, 8(3) , 394-401).
  • Protein tyrosine kinases can be broadly classified as receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g. c-src, Ick, Zap70) kinases. Inappropriate or uncontrolled activation of many of these kinase, i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
  • receptor e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr
  • non-receptor e.g. c-src, Ick, Zap70
  • P56lck and zap 70 are indicated in disease conditions in which T cells are hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection.
  • the process of angiogenesis has been associated with a number of disease states (e.g. tumourogenesis, psoriasis, rheumatoid arthritis) and this has been shown to be controlled through the action of a number of receptor tyrosine kinases (L.K. Shawver, DDT, 1997, 2(2) , 50-63).
  • EP0635507 discloses a class of tricyclic quinazoline derivatives of the formula: wherein R 1 and R 2 together form specified optionally substituted groups containing at least one heteroatom so as to form a 5 or 6-membered ring, in which there is a N atom at the 6 position of the quinazoline ring; R 3 includes independently hydrogen, hydroxy, halogeno, (1-4C)alkyl, (1-4C) alkoxy di-[(1-4C)alkyl]amino, or (2-4C)alkanoylamino.
  • WO 95/19774 discloses bicyclic derivatives of formula:
  • a to E are nitrogen or carbon and at least one of A to E is nitrogen; or two adjacent atoms together are N, O or S;
  • R 1 is H or alkyl and n is 0, 1 or 2;
  • m is 0 to 3 and
  • R 2 includes optionally substituted alkyl, alkoxy, cycloalkoxy, cycloalkoxy, or two R 2 groups together form a carbocycle or heterocycle.
  • the compounds are said to inhibit epidermal growth factor receptor tyrosine kinase and suggested uses include the treatment of cancer, psoriasis, kidney disease, pancreatitis and contraception.
  • WO 96/07657 discloses pyrimido[5,4-d]pyrimidine derivatives of formula wherein Ra includes hydrogen or alkyl; Rb includes optionally substituted phenyl; and Rc includes hydrogen, halo, alkyl, cycloalkyl, cycloalkylalkylaryl, aralkyl, OH, optionally substituted alkoxy, cycloalkoxy, aryloxy, aralkoxy, mercapto, optionally substituted alkyl- or arylsulfenyl, -sulfinyl, or -sulfonyl and substituted alkyleneimino; as EGF-R inhibitors.
  • WO 96/09294 discloses quinoline and quinazoline derivatives of formula wherein X is N or CH; Y includes O, S, CH 2 O and NH; R 6 includes phenoxy, benzyloxy, benzylmercapto, benzylamino, benzyl, anilino, benzoyl, anilinocarbonyl, anilinomethyl, phenylethynyl, phenylethenyl, phenylethyl, phenylthio, phenylsulphonyl, benzylthio, benzylsulphonyl, phenylthiomethyl, phenylsulphonylmethyl, phenoxymethyl, thienylmethoxy, furanylmethoxy, cyclohexyl, and cyclohexylmethoxy; and R 1 , R 2 , R 3 and R 3' include a range of possible substituents, predominantly not including heterocyclic
  • WO 96/15118 discloses quinazoline derivatives of formula wherein X includes O, S, SO, SO 2 , CH 2 , OCH 2 , CH 2 O and CO; Q includes a phenyl or naphthyl group and various 5- or 6-membered heteroaryl moieties; n is 0, 1, 2 or 3 and each R 2 is independently halogeno, trifluoromethyl, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkyl amino or C 2-4 alkanoylamino; m is 1, 2 or 3 and R 1 includes a range of possible substituents, predominantly not including heterocyclic ring systems; as receptor tyrosine kinase inhibitors, in particular as EGF-R inhibitors.
  • WO 96/15128 discloses pyrido[2,3-d]pyrimidine and naphthyridine derivatives of formula wherein X is CH or N; B is halo, hydroxy or NR 3 R 4 ; Ar includes unsubstituted and substituted phenyl or pyridyl; and R 1 , R 2 , R 3 and R 4 independently include hydrogen, amino, C 1-8 alkylamino, di-C 1-8 alkylamino, unsubstituted and substituted aromatic or heteroaromatic groups, and unsubstituted and substituted C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl groups.
  • WO 96/16960 discloses quinazoline derivatives of formula wherein m is 1 or 2; each R 1 independently includes hydrogen and C 1-4 alkoxy; n is 1, 2 or 3; each R 2 independently includes hydrogen, halogeno and C 1-4 alkyl, or R 2 is an aryl- or heteroaryl-containing group, including pyridylmethoxy and benzoyl; and Ar includes a substituted or unsubstituted 5- or 9-membered nitrogen-linked heteroaryl moiety containing up to four nitrogen atoms, in particular imidazol-1-yl, imidazolin-1-yl, benzimidazol-1-yl, pyrazol-1-yl and 1,2,4-triazol-1-yl; as receptor tyrosine kinase inhibitors, in particular as EGF-R inhibitors.
  • protein tyrosine kinase may not always provide optimal treatment of, for example tumours, and could in certain cases even be detrimental to subjects since protein tyrosine kinases provide an essential role in the normal regulation of cell growth.
  • protein tyrosine kinases such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, lck, Zap70, and fyn.
  • protein tyrosine kinases such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, lck, Zap70, and fyn.
  • the present invention relates to heterocyclic compounds which may be used to treat disorders mediated by protein tyrosine kinases and in particular have anti-cancer properties. More particularly, the compounds of the present invention are potent inhibitors of protein tyrosine kinases such as such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, and fyn, thereby allowing clinical management of particular diseased tissues.
  • protein tyrosine kinases such as such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, and fyn
  • the present invention envisages, in particular, the treatment of human malignancies, for example breast, non-small cell lung, ovary, stomach, and pancreatic tumours, especially those driven by EGFr or erbB-2, using the compounds of the present invention.
  • the invention includes compounds which are highly active against the c-erbB-2 protein tyrosine kinase often in preference to the EGF receptor kinase hence allowing treatment of c-erbB-2 driven tumours.
  • the invention also includes compounds which are highly active against both c-erbB-2 and EGF-R receptor kinases hence allowing treatment of a broader range of tumours.
  • the present invention envisages that disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity in a relatively selective manner, thereby minimising potential side effects.
  • the present invention provides a compound of formula (I): or a salt thereof; wherein
  • U represents an indolyl, isoindolyl, indolinyl, isoindolinyl, 1 H -indazolyl, 2,3-dihydro-1 H -indazolyl, 1 H -benzimidazolyl, 2,3-dihydro-1 H -benzimidazolyl or 1 H -benzotriazolyl group, which is substituted by at least one independently selected R 6 group and is optionally substituted by at least one independently selected R 4 group;
  • halo is meant fluoro, chloro, bromo or iodo.
  • Alkyl groups containing three or more carbon atoms may be straight, branched or cyclised.
  • X is N.
  • Y is NRa, NR a (CH 2 ), or (CH 2 )NR a , preferably Y is NRa and Ra is preferably hydrogen or methyl.
  • n is 0, p is 1 and R 1 is selected from the group comprising amino, C 1-4 alkylamino, diC 1-4 alkylamino, especially diC 1-4 alkylamino, most especially dimethylamino or methylethylamino.
  • M 4 represents SOR 13 , SO 2 R 13 , NR 12 SO 2 R 13 , CO 2 R 13 or CONR 14 R 15 in which R 12 and R 13 are defined above and R 14 and R 15 each independently represent H or C 1-4 alkyl; more preferably R 12 , R 13 , R 14 and R 15 each independently represent H or methyl.
  • M 5 represents a group NR 14 R 15 in which R 14 and R 15 together with the nitrogen atom to which they are attached represent a 6-membered ring optionally containing an additional heteroatom selected from N or O, in which ring any nitrogen atom present may optionally be substituted with a C 1-4 alkyl group, preferably a methyl group; or M 5 represents a group in which t represents 2 or 3 and R 16 represents OH, NH 2 , N(C 1-4 alkyl) 2 or OC 1-4 alkyl; more preferably R 16 represents NH 2 or N(CH 3 ) 2 .
  • M 2 -M 3 -M 4 represents an ⁇ -amino carboxylic acid or a methyl ester or amide thereof.
  • M 2 -M 3 -M 4 represents a methylsulphonylethylamino, methylsulphinylethylamino, methylsulphonylpropylamino, methylsulphinylpropylamino, methylsulphonamidoethylamino, sarcosinamide, glycine, glycinamide or glycine methyl ester group.
  • M 5 represents a piperazinyl, methylpiperazinyl, piperidinyl, prolinamido or N,N -dimethylprolinamido group.
  • M 5 represents an isopropylamino or N-morpholinyl group.
  • M 1 -M 5 represents an isopropylacetamido or N-morpholinoacetamido group.
  • M 2 -M 3' -M 6 represents a pyridylamino, cyclopropylamino, N-(piperidin-4-yl)-N-methylamino, N,N-dimethylaminoprop-2-ylamino, N-(2-dimethylaminoethyl)-N-ethylamino or tetrahydrofuranomethylamino group, preferably a pyridylamino group.
  • R" may be selected from the group comprising phenyl, furan, imidazole, tetrazole, triazole, pyrrolidine, piperazine, piperidine and oxadiazole.
  • R 4 is hydrogen, hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, di-[C 1-4 alkyl]amino, nitro or trifluoromethyl, preferably hydrogen, halogen or methyl, more preferably hydrogen.
  • R 6 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, pyridylmethyl, phenyl, benzenesulphonyl, phenoxy or fluorophenoxy.
  • R 6 is in the para position with respect to Y.
  • one or both of the rings comprising the bicyclic ring system U may be aromatic or non-aromatic.
  • the R 4 and R 6 groups may be bound to the ring system by either a carbon atom or a heteroatom of the ring system.
  • the ring system itself may be bound to the bridging group by a carbon atom or a heteroatom.
  • the system, but these groups are preferably bound to the ring which is not bound to the bridging group Y in such a case.
  • X represents N; p is 0; n is 1; and the group R" is in the 6-position of the pyridopyrimidine ring system.
  • a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NR a , wherein R a is hydrogen or C 1-4 alkyl; R" represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, triazole, dioxolane or a partially or fully hydrogenated derivative of any of these groups, optionally substituted by one or more R 1 groups selected from halo, C 1-4 alkyl, carboxy, formyl, hydroxy-C 1-4 alkyl, 1,3-dioxolan-2-yl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy-C 1-4 alkanoyl(C 1-4 alkyl)amino, C 1-4 alkyla
  • a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NR a , wherein R a is hydrogen or C 1-4 alkyl; R" represents furan, thiophene, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, triazole, dioxolane or a partially or fully hydrogenated derivative of any of these groups, optionally substituted with an R 1 group selected from methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl, methylsulphinylethylamino-carbonyl, methylsulphonylpropylamino-methyl, methylsulphinylpropylamino-methyl, methylsulphonylpropylamino-methyl,
  • a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NR a wherein R a is hydrogen or C 1-4 alkyl; n is 0; each R 1 group is selected from hydrogen, halo, C 1-4 alkyl, carboxy, formyl, hydroxy-C 1-4 alkyl, 1,3-dioxolan-2-yl, benzyloxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, hydroxy-C 1-4 alkanoyl(C 1-4 alkyl)amino, C 1-4 alkylamino-C 1-4 alkyl, di(C 1-4 alkyl)amino-C 1-4 alkyl, methylsulphonylethylaminomethyl, methylsulphonylethylamino-carbonyl, methylsulphinylethylamino-methyl, methyls
  • a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NR a , wherein R a is hydrogen or C 1-4 alkyl; R" represents a furan, imidazole, triazole, oxadiazole, pyrrolidine, piperidine or piperazine ring, optionally substituted by one or more R 1 groups selected from 1,3-dioxolan-2-yl, formyl, carboxy, C 1-4 -alkyl, prolinamidomethyl, isopropylacetamido, N-morpholinylacetamido, methylsulphonylethylaminomethyl or methylsulphonylethylaminocarbonyl; p is 0; R 4 represents hydrogen or methyl; U represents indazolyl, indolyl or benzimidazolyl, more preferably indazolyl; and R 6 represents benzyl, fluor
  • a compound of formula (I) or a salt or solvate thereof wherein X represents N; Y represents NR a , wherein R a is hydrogen or C 1-4 alkyl; n is 0; each R 1 group is selected from hydrogen, halo, benzyloxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino or hydroxy-C 1-4 alkanoyl(C 1-4 alkyl)amino, more preferably dimethylamino; R 4 represents hydrogen or methyl; U represents indazolyl, indolyl or benzimidazolyl, more preferably indazolyl; and R 6 represents benzyl, fluorobenzyl, pyridylmethyl or benzenesulphonyl.
  • Preferred compounds of the present invention include:
  • Particularly preferred compounds of the present invention include:
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula (I).
  • the therapeutic activity resides in the moiety derived from the compound of the invention as defined herein and the identity of the other component is of less importance although for therapeutic and prophylactic purposes it is, preferably, pharmaceutically acceptable to the patient.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p -toluenesulphonic, acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p -toluenesulphonic, acids.
  • the compound of formula (II) as defined above is reacted with the appropriate reagents to substitute the groups R" and R 1 onto the ring A by replacement of the respective leaving groups and then the product thereby obtained (of formula (V) below) is reacted with the compound of formula (III) as defined above, followed, if desired, by conversion of the compound of formula (I) thereby obtained into another compound of formula (I).
  • the compound of formula (V) may be prepared by the reaction of a compound of formula (VI) with appropriate reagents to substitute the group(s) R 1 and the group R" onto the ring A to prepare a compound of formula (VII) and subsequent reaction to incorporate the leaving group L.
  • a chloro leaving group can be incorporated by reaction of a corresponding 3,4-dihydropyrimidone with carbon tetrachloride/triphenylphosphine in an appropriate solvent.
  • the group R" may, therefore, be substituted onto the ring A by replacement of a suitable leaving group.
  • This is especially suitable for preparing compounds where R" is a substituted or unsubstituted phenyl or heterocyclic ring system; such compounds may, for example, be prepared by reaction of the corresponding aryl or heteroaryl stannane derivative with the corresponding compound of formula (IV) carrying the leaving group L' in the appropriate position on the ring.
  • the group(s) R 1 may, therefore, also be substituted onto the ring A by replacement of suitable leaving group(s). This is especially suitable for preparing compounds of formula (I) wherein an R 1 group is linked to the ring A by a nitrogen atom; such compounds may, for example, be obtained by reaction of the amine corresponding to the group R 1 with the corresponding compound carrying a halo substituent in the appropriate position on the ring A.
  • the reagents used to effect the substitution of the groups R" and R 1 onto the ring A may, in certain circumstances, include appropriate protecting group(s) well known to the person skilled in the art for particular functionalities. This may, for example, be suitable where either of the groups R" or R 1 contain a free amino functionality. Such protecting group(s) would be removed by standard methods after the substitution onto the ring A has been effected.
  • protecting groups See T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd edn., John Wiley & Sons, New York, 1991.
  • Such processes are particularly suitable for the preparation of compounds of formula (I) wherein either R" carries or R 1 represents a substituent selected from M 1 -M 2 -M 3 -M 4 , M 1 -M 5 or M 1 -M 2 -M 3' -M 6 as defined above in which M 2 represents NR 12 .
  • the group Z carries a terminal formyl group (CHO).
  • the compound may be suitably prepared from the corresponding dioxolanyl substituted compound, for example by acid hydrolysis.
  • the dioxolanyl substituted compound may be prepared by reaction of a compound of formula (IV) with an appropriate reagent to substitute the relevant leaving group with the substituent carrying the dioxolanyl ring.
  • This reagent could, for example, be an appropriate heteroaryl stannane derivative.
  • Z carries a terminal formyl group
  • the compound could suitably be prepared by reaction of a compound of formula (IV) with an appropriate heteroaryl stannane derivative.
  • This derivative is either readily available or can be readily synthesised by those skilled in the art using conventional methods of organic synthesis.
  • Suitable possibilities for preparation of compounds where R" carries the aforementioned substituents include the following schematic examples:-
  • the resulting compounds would, for example, then be converted into the respective stannane derivative.
  • a suitable process may comprise reaction of the compound in which the group Z carries a terminal formyl group (i.e. a -CHO or -(C 1-3 alkylene)-CHO group) with a compound of formula HM 2 -M 3 -M 4 , a compound of formula HM 2 -M 3 -M 6 or a compound of formula HM 5 , wherein M 2 represents NR 12 .
  • the reaction preferably involves a reductive amination by means of an appropriate reducing agent, for example sodium triacetoxyborohydride.
  • a suitable process would comprise reaction of a compound in which the group Z carries a -(C 0-3 alkylene)-CO 2 H group with a compound of formula HM 2 -M 3 -M 4 , a compound of formula HM 2 -M 3' -M 6 or a compound of formula HM 5 , wherein M 2 represents NR 12 .
  • the group Z is converted into the group R" by a de novo synthesis of a substituted or unsubstituted heterocyclic ring system using appropriate reagents.
  • a de novo synthesis of a substituted or unsubstituted heterocyclic ring system using appropriate reagents would involve standard synthetic methodology known to the person skilled in the art for building up the heterocyclic ring system.
  • Z could suitably represent an alkyne group which when reacted with an appropriate nitrile oxide results in the formation of an isoxazole ring system; reaction with an azide would result in the formation of a triazole ring system.
  • the group Z could also suitably represent an amidoxime group (derived from a cyano group) which when reacted with an activated carboxylic acid derivative (such as an acid chloride or an acid imidazolide) would result in the formation of a 1,2,4-oxadiazole ring system.
  • the group Z could also suitably represent a bromomethylenecarbonyl group which would be reacted with an imidate to result in the formation of an oxazole ring system, with a guanidino group to result in the formation of an N-imidazole ring system or with an amidine group to result in the formation of a C-imidazole ring system.
  • the group Z could also suitably represent an activated carboxylic acid group which would be reacted to form a hydrazinoketone which would subsequently be reacted with another activated carboxylic acid derivative to result in the preparation of a 1,3,4-oxadiazole ring system.
  • Such processes are particularly suitable for the preparation of the compounds of formula (I) wherein R" carries a substituent selected from M 1 -M 2 -M 3 -M 4 , M 1 -M 5 or M 1 -M 2 -M 3' -M 6 as defined above in which M 2 represents CR 12 R 13 , including those in which in M 1 one CH 2 group is replaced by a CO group.
  • Such processes are especially suitable for the preparation of compounds of formula (I) wherein either (i) p is 0, n is 1 and R" carries a substituent selected from M 1 -M 2 -M 3 -M 4 , M 1 -M 5 or M 1 -M 2 -M 3' -M 6 as defined above in which M 2 represents CR 12 R 13 , or (ii) p is 1, n is 0 and R 1 is selected from M 1 -M 2 -M 3 -M 4 , M 1 -M 5 or M 1 -M 2 -M 3' -M 6 as defined above in which M 2 represents CR 12 R 13 .
  • Suitable leaving groups for L, L' and L" will be well known to those skilled in the art and include, for example, halo such as chloro and bromo; sulphonyloxy groups such as methanesulphonyloxy and toluene-p-sulphonyloxy; alkoxy groups; and triflate.
  • the coupling reaction referred to above with the compound of formula (III) is conveniently carried out in the presence of a suitable inert solvent, for example a C 1-4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone or acetonitrile at a non-extreme temperature, for example from 0 to 150°, suitably 10 to 100°C, preferably 50 to 100°C.
  • a suitable inert solvent for example a C 1-4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone or acetonitrile
  • a group R 1 may be substituted onto the ring A by replacement of another group R 1 which is a suitable leaving group.
  • This is especially suitable for preparing compounds of formula (I) wherein an R 1 group is linked to the ring A by a nitrogen atom; such compounds may, for example, be obtained by reaction of the amine corresponding to the group R 1 with the corresponding compound of formula (I) carrying a halo substituent in the appropriate position on the ring A.
  • a compound containing an alkyl or aryl mercapto group may be oxidised to the corresponding sulphinyl or sulphonyl compound by use of an organic peroxide (e.g. benzoyl peroxide) or suitable inorganic oxidant (eg OXONE ®).
  • an organic peroxide e.g. benzoyl peroxide
  • suitable inorganic oxidant e.g OXONE ®
  • a compound containing a nitro substituent may be reduced to the corresponding amino-compound, e.g. by use of hydrogen and an appropriate catalyst (if there are no other susceptible groups) or by use of Raney Nickel and hydrazine hydrate.
  • Amino or hydroxy substituents may be acylated by use of an acid chloride or an anhydride under appropriate conditions. Equally an acetate or amide group may be cleaved to the hydroxy or amino compound respectively by treatment with, for example, dilute aqueous base.
  • amino substituent may also be converted to a dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride.
  • a formyl substituent may be converted to a hydroxymethyl or a carboxy substituent by standard reduction or oxidation methods respectively.
  • the compounds of formula (I) and salts thereof have anticancer activity as demonstrated hereinafter by their inhibition of the protein tyrosine kinase c-erbB-2, c-erbB-4 and/or EGF-r enzymes and their effect on selected cell lines whose growth is dependent on c-erbB-2 or EGF-r tyrosine kinase activity.
  • the present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof for use in medical therapy, and particularly in the treatment of disorders mediated by protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above.
  • the compounds of the present invention are especially useful for the treatment of disorders caused by aberrant c-erbB-2 and/or EGF-r activity such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers, and psoriasis.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of psoriasis.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain for example 0.5mg to 1g, preferably 70mg to 700mg, more preferably 5mg to 100mg of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound, salt or solvate of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian.
  • an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate of the present invention may be determined as a proportion of the effective amount of the compound per se .
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other pharmaceutically active agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the optionally substituted bicyclic species and the specified amine were mixed in an appropriate solvent (acetonitrile unless otherwise specified), and heated to reflux. When the reaction was complete (as judged by tic), the reaction mixture was allowed to cool. The resulting suspension was diluted, e.g. with acetone, and the solid collected by filtration, washing e.g. with excess acetone, and dried at 60°C in vacuo , giving the product as the hydrochloride salt. If the free base was required ( e.g. for further reaction), this was obtained by treatment with a base e.g. triethylamine; purification by chromatography was then performed, if required.
  • an appropriate solvent acetonitrile unless otherwise specified
  • a suitable leaving group such as chloro, bromo, iodo or triflate
  • a suitable palladium catalyst such as bis-(triphenylphosphine)palladium (II) chloride or 1,4-bis(dip
  • Procedure (A) containing a suitable leaving group such as chloro
  • a suitable leaving group such as chloro
  • the cooled mixture was generally purified by chromatography on silica.
  • the relevant nitro-substituted 1H-indazole was treated with a base such as potassium carbonate or sodium hydroxide in a suitable solvent, such as acetone or acetonitrile.
  • a base such as potassium carbonate or sodium hydroxide
  • a suitable solvent such as acetone or acetonitrile.
  • the appropriate aryl halide or heteroaryl halide was added and the reaction mixture heated or stirred at room temperature overnight. Subsequent concentration in vacuo and chromatography on silica gave the desired 1-substituted nitro-1H-indazoles. Hydrogenation was carried out by analogy with the preparation of 5-amino-1-benzyl-1H-indole described above.
  • Amines prepared by such methods and specifically used in the preparation of the later Examples include: -
  • This material may subsequently be carried forward to the appropriately substituted pyridopyrimidine intermediate according to the procedures as described in WO95/19774, J. Med. Chem., 1996, 39, pp 1823-1835, and J. Chem. Soc., Perkin Trans. 1, 1996, pp 2221-2226.
  • Specific compounds made by such procedures include 6-chloro-pyrido[3,4-d]pyrimidin-one and 4,6-dichloro-pyrido[3,4-d]pyrimidine.
  • N -(4- N',N' -Dimethylaminopyrid-3-yl)-2,2-dimethylpropionamide (1.1g) in dry THF under N 2 at -70°C was treated with TMEDA (1.45g) and butyl lithium (1.6M, 8ml). The mixture was warmed to 0°C for three hours before being recooled to -70°C. Carbon dioxide was bubbled through the solution for 1 hour and the resulting solution was warmed to room temperature under a carbon dioxide atmosphere and stirred there for 16 hours. The resulting mixture was concentrated in vacuo and partitioned between ether and water.
  • 5-Amino-2-( N , N -dimethylamino)-pyridine-4-carboxylic acid (0.54g) was treated with formamidine acetate (3.12g) in glacial acetic acid (20ml) and heated at reflux for 16 hours. The mixture was cooled, evaporated to dryness in vacuo and partitioned between ethyl acetate and water.
  • 6-chloro-pyrido[3,4-d]pyrimidin-4-one (26.14g) was treated with 2N dimethylamine in ethanol (200ml) and heated at 130°C in a Parr bomb for 3 days. The cooled mixture was filtered and triturated from isopropanol to give the title compound (16.61g) as a yellow solid; m/z (M+1 + ) 191.
  • 6-Chloro-pyrido[3,4-d]pyrimidin-4-one (10g) in 1-methyl-2-pyrrolidinone (100ml) was treated with copper (I) iodide (10.52g) and potassium cyanide (7.10g) at 215°c for 72 hours under N 2 . Further potassium cyanide was added (3.58g) and heating continued at 230°C for 70 hours.
  • the 1-methyl-2-pyrrolidinone was removed by distillation at reduced pressure and the residue absorbed onto silica.
  • 6-Cyano-pyrido[3,4-d]pyrimidin-4-one (0.3g) in diglyme (2ml) was treated with tributyl tin azide (0.49g) at reflux under N 2 for 15 hours.
  • the cooled mixture was partitioned between ethyl acetate and water and the aqueous phase extracted further with ethyl acetate.
  • the aqueous phase was concentrated in vacuo , the residue taken up in methanol and inorganics removed by filtration.
  • 6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one (0.5g) was treated with phosphorus oxychloride at room temperature under N 2 . After 1 hour at room temperature and 1 hour at 50°C, the mixture was concentrated in vacuo, azeotroping with toluene, then taken up in ethyl acetate, washed with sodium bicarbonate solution, dried and concentrated in vacuo to give the title compound (0.17g) as an orange solid; ⁇ H CDCl 3 9.68 (1H,s), 9.30 (1H,s), 8.96 (1H,s), 2.75 (3H,s); m/z (M+1 + ) 248.
  • 6-Benzyloxy-4-hydroxy-pyrido[3,4-d]pyrimidine (1.033g, 4.1mmol) was suspended in thionyl chloride (10ml) under a nitogen atmosphere. DMF (3 drops) was added and the mixture was heated to reflux with stirring for 5.5 hours to give a dark solution, and then left to stand under nitrogen overnight. The mixture was concentrated in vacuo , azeotroping twice with toluene to remove all traces of thionyl cloride and acidic by-products.
  • the hydrochloride salt was partitioned between dichloromethane and 2N sodium carbonate. Extraction of the aqueous layer with dichloromethane was followed by drying of the organic phase and concentration in vacuo to give the free base.
  • Imidazole (0.8g) in dry DMSO was treated with sodium hydride (60%, 0.47g) and (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine in a reacti-vial and heated at 120°C. After 7 days, the mixture was poured onto water and extracted with ethyl acetate.
  • 1,2,4-triazole was reacted with (1-Benzyl-1 H-indazol-5-yl)-(6-chtoro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 20 to give the title compound; ⁇ H [ 2 H 6 ]DMSO 10.53(1H,s), 9.46(1H,s), 9.14(1H,s), 9.01(1H,s), 8.65(1H,s), 8.40(1H,s), 8.25(1H,s), 8.15(1H,s), 7.75(2H,s), 7.25(5H,m), 5.65(2H,s); m/z (M + ) 418.
  • 1,2,3-triazole was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 21 to give the title compound; ⁇ H [ 2 H 6 ]DMSO 10.62(1H,s), 9.24(2H,s), 8.73(1H,s), 8.33(3H,s), 8.21(1H,s), 7.80(1H,s), 7.33(5H,m), 5.73(2H,s); m/z (M + ) 420.
  • 1,2,3-triazole was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine as in Example 21 to give the title compound; ⁇ H [ 2 H 6 ]DMSO 10.53(1H,s), 9.28(1H,s), 9.13(1H,s), 8.89(1H,s), 8.64(1H,s), 8.23(1H,s), 8.10(1H,s), 8.00(1H,s), 7.69(2H,s), 7.23(5H,m), 5.62(2H,s); m/z (M + ) 420.
  • the microorganism was grown in SB1 medium at a temperature of 28°C. Flasks were shaken at 250rpm.
  • the SB1 culture medium consisted of Arkasoy (25g; British Arcady Company), Bacto yeast extract (5g; Difco Laboratories) and KH 2 PO 4 (5g) in distilled water (900ml).
  • the pH of the culture medium was adjusted to 7.2 using conc. NaOH prior to autoclaving (15min./121°C). 100ml of a 20% (w/v) solution of glucose (filter sterilised) was added post sterilisation.
  • N4-(1-Benzyl-1H-indazol-5-yl)-N6,N6-dimethyl-pyrido[3,4-d]pyrimidine-4,6-diamine (12.5mg) in methanol (1.0ml) was added to each culture flask after 72 hours growth. Cultures were harvested 7 days after compound addition.
  • the culture broth (2 x 50ml) was mixed with an equal volume of methanol (containing 0.6% (v/v) TFA), centrifuged (4000rpm, 4.C, 30min) and the supematant concentrated under a stream of nitrogen gas.
  • the resulting concentrated aqueous extract was adsorbed onto a water-equilibrated C18 SPE cartridge (2g; Varian Ltd., Walton-on Thames, UK) which was washed with water (5 volumes), then eluted with 3 x 5ml methanol (containing 0.3% (v/v) TFA).
  • the substrate phosphorylation assays use baculovirus expressed, recombinant constructs of the intracellular domains of c-erbB-2 and c-erbB-4 that are constitutively active and EGFr isolated from solubilised A431 cell membranes.
  • the method measures the ability of the isolated enzymes to catalyse the transfer of the ⁇ -phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide (Biotin-GluGluGluGluTyrPheGluLeuVal).
  • the enzyme is incubated for 30 minutes, at room temperature, with 10mM MnCl 2 , ATP and peptide at Km concentrations, and test compound (diluted from a 5mM stock in DMSO, final DMSO concentration is 2%) in 40mM HEPES buffer, pH 7.4.
  • the reaction is stopped by the addition of EDTA (final concentration 0.15mM) and a sample is transferred to a streptavidin-coated 96-well plate.
  • the plate is washed and level of phosphotyrosine on the peptide is determined using a Europium-labelled antiphosphotyrosine antibody and quantified with a time-resolved fluorescence technique.
  • Table 1 The results are shown in Table 1 as the IC 50 values in nM.

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